Prion diseases are neurodegenerative diseases of humans and animals, which are invariably fatal and lead to death within a year after onset of clinical symptoms. As with most other neurodegenerative diseases, no effective therapy is known. Potential therapeutics proposed for treatment of prion diseases include polysulfated anions, dextrans, and cyclic tetrapyrroles have been shown to increase survival time when given prior to prion infection in rodents, but not when given after infection has been initiated. Besides studies in rodents, mouse neuroblastoma (ScN2a) cells chronically infected with scrapie prions have been used to identify several candidate antiprion drugs but none of these drugs has been shown to be effective in halting prion diseases in either animals or humans. Based on recently published laboratory studies using cultured cells and a pilot clinical study in progress, we propose to perform a series of therapeutic-based experiments in transgenic (Tg) and non-Tg mice. Tg mice overexpressing (1) mouse (M) prion protein (PrP), (2) bovine (Bo) PrP or (3) a chimeric human-mouse PrP designated either MHu2M(M165V, E167Q) or MHu2M(M165V) will be used in these studies. Tg and non-Tg mice will be used to evaluate the toxicity of quinacrine isomers and a series of new compounds that are at least 10-fold more efficacious as determined in ScNa cells. After acute, short-term and longterm toxicity studies, treatment protocols for mice inoculated with prions will be initiated. Mice will begin to receive one of the quinacrine isomers or a new compound at point when 50%, 75% or 85% of the incubation time has elapsed. In most cases, the mice will be treated for 30 days. Two different strains of mouse or human prions will be used in these studies. Besides neuropathologic studies, samples of blood, muscle and brain will be taken for immunoassay determinations of PrP sc. The results of these studies are likely to provide important data leading toward the development of an effective therapeutic regimen for prion diseases in humans.